CRUK RadNet Glasgow Centre

RT has profound effects on both tumour cells and the tumour microenvironment (TME). These can evolve during treatment and alter treatment outcomes. Remodelling of the microenvironment can also impact on tumour growth rate, invasion and metastasis. We are using preclinical studies and human tissue samples to understand the RT-mediated processes that occur in response to treatment and/or alter treatment outcomes to identify targets for intervention and predictive biomarkers. Analysing dynamic treatment response data could also identify patients at high risk of recurrence. Crucially, these data could allow intensification of therapy for high-risk patients. Therefore, we are investing in longitudinal collection and analysis of imaging data and biospecimens from patients and mice undergoing RT-based treatments.

RT outcomes are dictated by complex interactions between irradiated tumours and their microenvironments, while toxicity in surrounding normal tissues is also driven by activation of signalling pathways involving multiple cell types. Understanding these interactions requires spatial interrogation of tumours and adjacent tissues. The Spatial Biology and Deep Phenotyping facilities in the centre provide the platform to study them at cellular and subcellular scale, allowing us to characterise radiation responses within and across tumours and their environments, including stroma, vasculature, and immune cells. Our overarching aim is to understand the tumour and normal tissue response to RT, at both a spatial and temporal level, in preclinical models of key tumour sites, and in clinical samples where available.

Integrating preclinical and clinical data, we aim to spatially characterise transcriptional, metabolic and immunological responses to RT in pancreatic cancer, rectal cancer, GBM, and liver cancer models to create new understanding of the differential effects of RT in different TME contexts. We are also studying the impact of RT and the TME on invasion and metastasis across different contexts. This approach will identify novel therapeutic targets and inform preclinical and clinical development of existing radiotherapeutic approaches, particularly in combination with targeted therapies.

Dr Joanna Birch, Senior Research Fellow (University of Glasgow) 

Professor Thomas Bird, Senior Lecturer (CRUK Scotland Institute) 

Professor Leo Carlin, Professor of Leukocyte Dynamics (CRUK Scotland Institute)

Professor Anthony Chalmers, Chair of Clinical Oncology (University of Glasgow) 

Professor Vincenzo D'Angiolella, Charles and Ethel Barr Chair of Cancer Research (University of Edinburgh)

Professor Gareth Inman 

• Professor (CRUK Scotland Institute)
• Director of Research (School of Cancer Sciences)
• Associate Dean of Research (MVLAS College Senior Management)

Professor John Le Quesne, Professor in Molecular Pathology (University of Glasgow)

Professor David Lewis, Professor of Molecular Imaging (CRUK Scotland Institute)

Dr Thomas MacVicar, Senior Lecturer (CRUK Scotland Institute) 

Dr Stephanie May, Honorary Lecturer (University of Glasgow) 

Professor Jen Morton, Professor (CRUK Scotland Institute)

Dr Adam Peters, Clinical Research Fellow (University of Glasgow)

Professor Campbell Roxburgh, Professor of Colorectal Surgical Oncology (University of Glasgow) 

Dr Colin Steele, Clinical Senior Lecturer/ Honorary Consultant in Surgery (Clinical Research Garscube)

Dr David Sumpton, Honorary Senior Lecturer (University of Glasgow) 

Dr Mathias Tesson, Post-doctoral Researcher (CRUK Scotland Institute) 

Dr Johan Vande Voorde, Senior Research Fellow (University of Glasgow) 

Dr Conchita Vens, Reader in Translational Radiobiology (University of Glasgow)

Pancreatic cancer is one of the deadliest epithelial malignancies, predicted to be the second most common cause of cancer death within the next decade. Less than 8% of patients survive their disease for five years, and despite significant investment in clinical trials, current therapies are largely ineffective. A prominent feature of pancreatic cancer is the dense fibrotic stroma that surrounds and supports the tumour cells and can account for up to 90% of the tumour volume. This microenvironment consists of fibroblasts and extracellular matrix (ECM) proteins as well as significant inflammation but a dearth of effector T cells. Each component plays an important role in pancreatic cancer progression, influencing tumour cell proliferation and survival, metabolism, migration, and immune surveillance.

The use of radiotherapy in pancreatic cancer treatment has been limited thus far; however, this may be due to a lack of understanding of the effect of radiation on the pancreatic TME. For example, RT can drive the release of inflammatory cytokines and chemokines which can result in altered fibroblast secretory output, ECM remodelling, macrophage polarisation and a more immunosuppressive and treatment resistant microenvironment. Having a clearer understanding of the complex signalling between different stromal cell subtypes should allow us to develop rational stromal targeting strategies for this disease. Thus, we are assessing the effects of radiotherapy on the pancreatic TME and investigating the associated signalling pathways that drive microenvironmental changes to identify novel radiosensitising targets. We are using clinically relevant mouse models in combination with spatial transcriptomics and mIF to provide highly multiplexed spatial resolution of gene expression. We will then triage identified targets of interest, validate in human tissue and perform functional interrogation in vitro prior to testing novel treatment regimens in vivo.

We are also investigating a specific type of post-translational modification which may affect the immune response to irradiation, particularly in terms of abscopal effects, and may be applicable across tumour types. We are conducting radiotherapy treatments on mice transplanted with tumour cells in which a key molecule in this pathway has been deleted and assessing the effects on the tumour and stromal cells in irradiated tumours and non-irradiated tumours in the same mice to assess abscopal response.

• Cancer Research UK
• Pancreatic Cancer UK
• UK Research and Innovation (UKRI)

• CRUK Scotland Institute Strategy Group: “Targeting energetic stress and tumour microenvironment following radiotherapy”
• Trans-Atlantic Pancreatic Cancer Alliance
• MRC National Mouse Genetics Network
• CRUK Scotland Centre
• UKRI Engineering Biology Mission Hub - Engineered Genetic Control Systems for Advanced Therapeutics